HGPS and Normal Aging
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal dominant disorder characterized by rapid, premature aging in children. Typically, affected children succumb to cardiovascular diseases, like heart attack or stroke, in their early teens. In addition to the severe cardiovascular diseases, HGPS patients experience problems with many other organ systems including the skin, fat and bone.
HGPS is caused by a C to T mutation in the 11th exon of the lamin A gene (LMNA) which leaves the protein code unchanged, instead activating a cryptic splice site. When used, this splice site removes the last 150 nucleotides from the 11th exon, resulting in an internal 50 amino acid deletion in the lamin A protein. This deletion interferes with post-translational processing by removing a key protease cleavage site, leading to permanent farnesylation and aberrant anchorage of the mutant lamin A, termed progerin, to the nuclear membrane. The abnormal presence of progerin disrupts the integrity of the nucleoskeleton, causing high levels of nuclear abnormalities, including nuclear blebbing, altered chromatin organization, transcriptional changes and aberrant mitosis.
Mitochondria are complex organelles that are believed to play a significant role in biological aging. They form a sophisticated, dynamic, tubular network that moves along microtubules and actin fibers. Mitochondria undergo a delicate balance between fusion and fission to maintain a functional population, where dysfunctional mitochondria are removed via autophagy and destroyed while new mitochondria are created to replace them. Dysfunctional mitochondria can cause systemic problems, increasing amounts of reactive oxygen species (ROS), and triggering DNA and protein damage.
Due to their ability to induce cellular distress as they accrue damage, mitochondria are believed to play a role in biological aging. PGC-1α, a transcription factor and key regulator of mitochondrial biogenesis has been found to be dramatically down-regulated by nearly 40 folds in HGPS iPSC-derived adipocytes compared to control adipocytes. HGPS patient cells have also been shown to exhibit increased ROS levels in multiple tissues. In addition, a marked downregulation of mitochondrial oxidative phosphorylation proteins and a reduced ATP have been reported in HGPS fibroblasts as well as in progeria mouse models. These evidences suggest that the mitochondria in HGPS cells might be dysfunctional.
It is known that the proper mitochondrial functions are guaranteed by their structural integrity. However, to date, the information on the structure and behavior of mitochondria in HGPS cells remains incomplete. More importantly, it remains unclear that, to what extent, the mitochondrial dysfunction contributes to the premature aging phenotypes in HGPS cells. Clearly, there is a need to better characterize the contribution of mitochondrial dysfunction to both aging, and even premature aging (progeria), and to provide a method for treating this dysfunction, and, consequently, age-related conditions generally.
Further, it is now known that the effects of the improperly processed version of the lamin A protein, called progerin, that accumulates in HGPS cells and wreaks havoc on cellular form and function, may be mitigated by rapamycin and analogues thereof. Moreover, several studies have shown that normal human cells also express tiny amounts of progerin, which accumulates as a person ages, and that rapamycin is effective in degrading and clearing progerin by stimulating autophagy as well as slowing senescence and reducing or abolishing a reduced integrity of the nuclear scaffold, i.e., nuclear blebbing.
Thus, a need exists for a method for alleviating the symptoms of both HGPS and normal aging, including inducing clearance of progerin from aging cells.
A need also exists for a compound or composition for alleviating the symptoms of both HGPS and normal aging, including clearance of progerin from aging cells.
Further, a need exists for a method and compound or composition for alleviating the symptoms of both HGPS-aging and normal aging in mammalian skin, particularly human skin.